tbuckley/cabot-search huggingface dataset:
Novel <i>SOX10</i> indel mutations drive schwannomas through impaired transactivation of myelination gene programs
Authors: Erik A Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas O Stevers, Abigail K Suwala, Chibo Hong, Somang Kim, Jimmy Bo Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope G Lucas, Emily Chan, Melike Pekmezci, Philip E LeBoit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen M Basnet, Robert J B Macaulay, Patrick Malafronte, Han Lee, William H Yong, Kevin Jon Williams, Tareq A Juratli, Douglas A Mata, Richard S P Huang, Matthew C Hiemenz, Dean C Pavlick, Garrett M Frampton, Tyler Janovitz, Jeffrey S Ross, Susan M Chang, Mitchel S Berger, Line Jacques, Jun S Song, Joseph F Costello, David A Solomon
Journal: Neuro-Oncology (2023)

Abstract Background Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. Methods We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. Results We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. Conclusions We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
Clinical Characteristics and Outcomes of Patients With <i>Cutibacterium acnes</i> Endocarditis
Authors: Floris J. Heinen, Florent Arregle, Floris S. van den Brink, Nina Ajmone Marsan, Lucas Bernts, Patrick Houthuizen, Otto Kamp, Nienke Roescher, Naomi Timmermans, Nelianne Verkaik, Jolien Roos-Hesselink, Marco C Post, Gilbert Habib, Wilco Tanis
Journal: JAMA Network Open (2023)

Importance It is suggested that patients with Cutibacterium acnes endocarditis often present without fever or abnormal inflammatory markers. However, no study has yet confirmed this statement. Objective To assess the clinical characteristics and outcomes of patients with C acnes endocarditis. Design, Setting, and Participants A case series of 105 patients presenting to 7 hospitals in the Netherlands and France (4 university hospitals and 3 teaching hospitals) with definite endocarditis according to the modified Duke criteria between January 1, 2010, and December 31, 2020, was performed. Clinical characteristics and outcomes were retrieved from medical records. Cases were identified by blood or valve and prosthesis cultures positive for C acnes , retrieved from the medical microbiology databases. Infected pacemaker or internal cardioverter defibrillator lead cases were excluded. Statistical analysis was performed in November 2022. Main Outcomes and Measures Main outcomes included symptoms at presentation, presence of prosthetic valve endocarditis, laboratory test results at presentation, time to positive results of blood cultures, 30-day and 1-year mortality rates, type of treatment (conservative or surgical), and endocarditis relapse rates. Results A total of 105 patients (mean [SD] age, 61.1 [13.9] years; 96 men [91.4%]; 93 patients [88.6%] with prosthetic valve endocarditis) were identified and included. Seventy patients (66.7%) did not experience fever prior to hospital admission, nor was it present at hospitalization. The median C-reactive protein level was 3.6 mg/dL (IQR, 1.2-7.5 mg/dL), and the median leukocyte count was 10.0 × 10 3 /µL (IQR, 8.2-12.2 × 10 3 /µL). The median time to positive blood culture results was 7 days (IQR, 6-9 days). Surgery or reoperation was indicated for 88 patients and performed for 80 patients. Not performing the indicated surgical procedure was associated with high mortality rates. Seventeen patients were treated conservatively, in accordance with the European Society of Cardiology guideline; these patients showed relatively high rates of endocarditis recurrence (5 of 17 [29.4%]). Conclusions and Relevance This case series suggests that C acnes endocarditis was seen predominantly among male patients with prosthetic heart valves. Diagnosing C acnes endocarditis is difficult due to its atypical presentation, with frequent absence of fever and inflammatory markers. The prolonged time to positivity of blood culture results further delays the diagnostic process. Not performing a surgical procedure when indicated seems to be associated with higher mortality rates. For prosthetic valve endocarditis with small vegetations, there should be a low threshold for surgery because this group seems prone to endocarditis recurrence.
Management of Locally Advanced Rectal Cancer—Building the Plane as We Fly
Authors: Shanglei Liu, Sonia Ramamoorthy
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2‐positive gastric cancer
Authors: Xingbin Hu, Zhenfeng Ma, Beibei Xu, Shulong Li, Zhiqi Yao, Bishan Liang, Jiao Wang, Wangjun Liao, Li Lin, Chunling Wang, Siting Zheng, Qijing Wu, Qiong Huang, Le Yu, Fenghua Wang, Min Shi
Journal: Cancer Communications (2023)

Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor-derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B (NF-κB) p65 and drove GLS1 microvesicle secretion through IQ motif-containing GTPase-activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro-angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2-positive gastric cancer. A combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.
Echocardiography phenotypes of right ventricular involvement in COVID-19 ARDS patients and ICU mortality: post-hoc (exploratory) analysis of repeated data from the ECHO-COVID study
Authors: Stephen Huang, Antoine Vieillard-Baron, Bruno Evrard, Gwenaël Prat, Michelle S. Chew, Martin Balik, Fernando Clau-Terré, Daniel De Backer, Armand Mekontso Dessap, Sam Orde, Andrea Morelli, Filippo Sanfilippo, Cyril Charron, Philippe Vignon, Michel Slama, Julien Maizel, Yoann Zerbib, Clement Brault, Ségolène Tran, François Bagate, Paul Masi, Gisèle Banauch, S. Banauch-Mayer, Bernard Cholley, S. Clavier, I. Ma, Marine Goudelin, Pierre Bailly, Laetitia Bodenes, Nicolas Ferriere, Patrick-Johansson Blixt, H. Didriksson, Paul Mayo, Anthony McLean, Anne-Marie Welsh, Luigi La Via, Veronica Dezio, J. B. Rius, Fernando Piscioneri, S. Gigliori, Arnaud Desachy, Anne-Laure Fedou, Bruno François, Thomas Daix, Marine Goudelin
Journal: Intensive Care Medicine (2023)
Lifetime Incidence of Treated Mental Health Disorders and Psychotropic Drug Prescriptions and Associated Socioeconomic Functioning
Authors: Lars Vedel Kessing, Simon Christoffer Ziersen, Avshalom Caspi, Terrie E. Moffitt, Per Kragh Andersen
Journal: JAMA Psychiatry (2023)

Few studies have estimated the lifetime incidence of mental health disorders and the association with socioeconomic functioning.
Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
Authors: Xin‐Yu Chen, Bin Li, Ye Wang, Juan Jin, Yu Yang, Lei‐Huan Huang, Meng‐Di Yang, Jian Zhang, Bi‐Yun Wang, Zhi‐Ming Shao, Ting Ni, Sheng‐Lin Huang, Xi‐Chun Hu, Zhong‐Hua Tao
Journal: Cancer Communications (2023)

Abstract Background Immune checkpoint inhibitors (ICIs) shed new light on triple‐negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. Methods Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8 + T cells, and transcriptional regulators of programmed cell death‐ligand 1 ( PD‐L1 ). Human peripheral blood mononuclear cell (Hu‐PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA‐sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase‐accessible chromatin sequencing were used to determine chromatin‐binding and accessibility. Results The epigenetic modulator AT‐rich interaction domain 1A ( ARID1A ) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8 + T cell infiltration and activity through upregulating PD‐L1. However, ARID1A did not directly regulate PD‐L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 ( NPM1 ) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD‐L1 transcription. In Hu‐PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency‐induced AIR in TNBC by reducing tumor malignancy and activating anti‐tumor immunity. In CTR20191353, ARID1A‐low patients derived more benefit from pucotenlimab compared to ARID1A‐high patients. Conclusions In AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD‐L1 axis, leading to poor outcome but sensitivity to ICI treatment.
Trends in Acute Care Use for Mental Health Conditions Among Youth During the COVID-19 Pandemic
Authors: Lindsay Overhage, Ruth Hailu, Alisa B. Busch, Ateev Mehrotra, Kenneth A. Michelson, Haiden A. Huskamp
Journal: JAMA Psychiatry (2023)

<h3>Importance</h3> Understanding how children's utilization of acute mental health care changed during the COVID-19 pandemic is critical for directing resources. <h3>Objective</h3> To examine youth acute mental health care use (emergency department [ED], boarding, and subsequent inpatient care) during the second year of the COVID-19 pandemic. <h3>Design, Setting, and Participants</h3> This cross-sectional analysis of national, deidentified commercial health insurance claims of youth mental health ED and hospital care took place between March 2019 and February 2022. Among 4.1 million commercial insurance enrollees aged 5 to 17 years, 17 614 and 16 815 youth had at least 1 mental health ED visit in the baseline year (March 2019-February 2020) and pandemic year 2 (March 2021-February 2022), respectively. <h3>Exposure</h3> The COVID-19 pandemic. <h3>Main outcomes and measures</h3> The relative change from baseline to pandemic year 2 was determined in (1) fraction of youth with 1 or more mental health ED visits; (2) percentage of mental health ED visits resulting in inpatient psychiatry admission; (3) mean length of inpatient psychiatric stay following ED visit; and (4) frequency of prolonged boarding (≥2 midnights) in the ED or a medical unit before admission to an inpatient psychiatric unit. <h3>Results</h3> Of 4.1 million enrollees, 51% were males and 41% were aged 13 to 17 years (vs 5-12 years) with 88 665 mental health ED visits. Comparing baseline to pandemic year 2, there was a 6.7% increase in youth with any mental health ED visits (95% CI, 4.7%-8.8%). Among adolescent females, there was a larger increase (22.1%; 95% CI, 19.2%-24.9%). The fraction of ED visits that resulted in a psychiatric admission increased by 8.4% (95% CI, 5.5%-11.2%). Mean length of inpatient psychiatric stay increased 3.8% (95% CI, 1.8%-5.7%). The fraction of episodes with prolonged boarding increased 76.4% (95% CI, 71.0%-81.0%). <h3>Conclusions and relevance</h3> Into the second year of the pandemic, mental health ED visits increased notably among adolescent females, and there was an increase in prolonged boarding of youth awaiting inpatient psychiatric care. Interventions are needed to increase inpatient child psychiatry capacity and reduce strain on the acute mental health care system.
Beyond Suppressing Testosterone: A Categorical System to Achieve a “Level Playing Field” in Sport
Authors: Katerina Jennings, Esther Braun
Journal: The American Journal of Bioethics (2023)

Regulations implemented by World Athletics (WA) require female athletes with differences of sexual development to suppress their blood testosterone levels in order to participate in certain women's sporting competitions. These regulations have been justified by reference to fairness. In this paper, we reconstruct WA's understanding of fairness, which requires a "level playing field" where no athlete should have a significant performance advantage based on factors other than talent, dedication, and hard work over an average athlete in their category. We demonstrate that by placing regulations only on testosterone levels, while ignoring physical as well as socioeconomic advantages, WA consistently fails to meet its own definition of fairness. We then discuss several ways in which this definition could be met. Our analysis shows that a categorical system, in which athletes are divided into categories based on properties leading to significant performance advantages, is best suited for meeting WA's definition of fairness.
PCR‐Free Innovative Strategies for SARS‐CoV‐2 Detection
Authors: Paolo Calorenni, Antonio A. Leonardi, Emanuele L. Sciuto, Maria G. Rizzo, Maria J. Lo Faro, Barbara Fazio, Alessia Irrera, Sabrina Conoci
Journal: Advanced Healthcare Materials (2023)

The pandemic outbreak caused by SARS-CoV-2 coronavirus brought a crucial issue in public health causing up to now more than 600 million infected people and 6.5 million deaths. Conventional diagnostic methods are based on quantitative reverse transcription polymerase chain reaction (RT-qPCR assay) and immuno-detection (ELISA assay). However, despite these techniques have the advantages of being standardized and consolidated, they keep some main limitations in terms of accuracy (immunoassays), time/cost consumption of analysis, the need for qualified personnel, and lab constrain (molecular assays). There is crucial the need to develop new diagnostic approaches for accurate, fast and portable viral detection and quantification. Among these, PCR-free biosensors represent the most appealing solution since they can allow molecular detection without the complexity of the PCR. This will enable the possibility to be integrated in portable and low-cost systems for massive and decentralized screening of SARS-CoV-2 in a point-of-care (PoC) format, pointing to achieve a performant identification and control of infection. In this review, the most recent approaches for the SARS-CoV-2 PCR-free detection are reported, describing both the instrumental and methodological features, and highlighting their suitability for a PoC application.
Opioids No Better Than Placebo at Relieving Back Pain
Authors: Emily Harris
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Hierarchically Released Liquid Metal Nanoparticles for Mild Photothermal Therapy/Chemotherapy of Breast Cancer Bone Metastases via Remodeling Tumor Stromal Microenvironment
Authors: Yaping Shen, Yang Zou, Binglin Bie, Yonggang Lv
Journal: Advanced Healthcare Materials (2023)

Abstract Currently, the treatment strategy for bone metastasis is mainly to inhibit the growth of tumor cells and the activity of osteoclasts, while ignoring the influence of the tumor stromal microenvironment (TSM) on the progression of bone metastasis. Herein, a dual‐target liquid metal (LM)‐based drug delivery system (DDS) with favorable photothermal performance is designed to spatially program the delivery of multiple therapeutic agents to enhance the treatment of bone metastasis through TSM remodeling. Briefly, mesoporous silicon‐coated LM is integrated into zeolitic imidazolate framework‐8 (ZIF‐8) with both bone‐seeking and tumor‐targeting capacities. Curcumin (Cur), a tumor microenvironment modulator, is encapsulated into ZIF‐8, and doxorubicin (DOX) is enclosed inside mesoporous silicon. Specific accumulation of the LM‐based DDS in bone metastases first relieves the tumor stroma by releasing Cur in response to the acidic tumor microenvironment and then releases DOX deep into the tumor under near‐infrared light irradiation. The combined strategy of the LM‐based DDS and mild photothermal therapy has been shown to effectively restrain cross‐talk between osteoclasts and tumor cells by inhibiting the secretion of transforming growth factor‐β, degrading extracellular matrix components, and increasing infiltration of CD4 + and CD8 + T cells, which provides a promising strategy for the treatment of bone metastases.
Potential Avoidable Costs of Low-Value Clinical Practices in Acute Injury Care in an Integrated Canadian Provincial Trauma System
Authors: Blanchard Conombo, Jason R. Guertin, Jeffrey S. Hoch, François Lauzier, Alexis F. Turgeon, Henry T. Stelfox, Lynne Moore
Journal: JAMA Surgery (2023)

This economic evaluation estimated the direct health care costs associated with 11 low-value clinical practices in acute trauma care in the integrated health care system of Quebec, Canada.